Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG.

BACKGROUND: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil+adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm. PATIENTS AND METHODS: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial. RESULTS: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P=0.87) or OS (hazards ratio: 0.98, P=0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively. CONCLUSION: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.

Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952.

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

Results of a randomised phase II study of cisplatin plus 5-fluorouracil versus cisplatin plus 5-fluorouracil with alpha-interferon in metastatic pancreatic cancer: an EORTC gastrointestinal tract cancer group trial.

A randomised phase II study of 5-fluorouracil (5-FU) plus cisplatin (CDDP) with or without alpha-interferon 2b was performed in patients with pancreatic cancer with measurable metastatic disease outside the pancreas. The treatment in arm A consisted of cisplatin (100 mg/m(2)) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m(2) for 4 days and in arm B the same treatment was given plus alpha-interferon 2b in a dose of 3 million Units/day subcutaneously (s.c.) from day 1 for 5 days. 36 patients were entered in the trial, 18 in each arm. In arm B only 15 patients were eligible. No responses were observed in the 5-FU/CDDP arm and only 2 partial responses were achieved in the interferon-arm, lasting 27 and 32 weeks, respectively. Both treatment arms showed considerable toxicity. It has to be concluded that both treatment regimens have little activity and cannot be recommended.

Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus.

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group.

OBJECTIVE: The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. SUMMARY BACKGROUND DATA: A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS: Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS: Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. CONCLUSIONS: Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region.

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group, the Gruppo Interdisciplinare Valutazione Interventi in Oncologia, and the Japanese Foundation for Cancer Research.

BACKGROUND: There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS: 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS: 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION: PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Final results of a phase III clinical trial on adjuvant intraportal infusion with heparin and 5-fluorouracil (5-FU) in resectable colon cancer (EORTC GITCCG 1983-1987). European Organization for Research and Treatment of Cancer. Gastrointestinal Tract Cancer Cooperative Group.

In this phase III clinical trial conducted by the Gastrointestinal Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (GITCCG-EORTC), we evaluated the effect of adjuvant intraportal infusion of heparin (HEP) and 5-fluorouracil (5-FU) on overall survival, disease-free survival and time to progression in patients with resectable colon cancer. From January 1983 to June 1987, 235 patients were randomised from 14 institutions in seven European countries: 79 patients made up the control group (control): 72 the portal vein infusion group given heparin alone (5000 IU daily x 7 consecutive days) (HEP); 84 the portal vein infusion group given heparin (5000 IU daily x 7 consecutive days) and 5-FU (500 mg/m2 daily x 7 consecutive days) (HEP/5-FU); 34 patients were considered ineligible. The 199 patients considered eligible were well balanced for age, sex, Karnofsky index, tumour location, surgery, surgical procedure and Dukes' stage. Four patients (2 control, 1 HEP, 1 HEP/5-FU) died of surgical complications. No differences were observed between control group and treatment groups (HEP, HEP/5-FU) for postoperative complications and number of hospitalisation days. Severe toxicity (grade 3-4, WHO) was found in 12% of patients in the HEP group and 8% in the HEP/5-FU group. After a median follow-up of 9 years, disease progression was reported in 40% of patients in the control group, 40% in the HEP group and 29% in the HEP/5-FU group. Five-year survival, time to progression and disease-free survival were 69%, 58% and 56%, respectively, in the control arm, 61%, 58% and 56% in the HEP arm, and 71%, 69% and 65% in the HEP/5-FU arm. Based on all randomised patients, the effect of treatment was not statistically significant with respect to any of the endpoints. It is confirmed that intraportal 5-FU infusion is safe and has a tolerable toxicity, but cannot be considered standard treatment for patients with resectable colon cancer.

Activity of cefotiam in combination with beta-lactam antibiotics on enterobacterial hospital strains.

By using checkerboard titrations the effect of cefotiam combined with different beta-lactam antibiotics on fifty strains of Enterobacteriaceae moderately susceptible (minimal inhibiting concentration greater than or equal to 8 mg/l) or resistant (minimal inhibiting concentration greater than or equal to 64 mg/l) to cefotiam was evaluated. The following compounds were tested: cefamandole, cefazolin, cefmenoxime, cefotaxime, cefotiam, ceftazidime, cefuroxime, mecillinam and piperacillin. The synergistic effect varied markedly. The combination cefotiam-mecillinam showed the highest rate of synergistic activity. Antagonism was found in 1% of the combinations.